Huntington's disease (HD) is a devastating chronic neurodegenerative disorder. No effective treatment is available and the disease is universally fatal. HD is caused by a highly penetrant, autosomal dominant mutation in the HD gene. To better understand the biologic affects of mutant htt expression and the early involvement of the dorsal striatum, we determined the changes in microRNA (miR) expression in normal human dorsal striatum versus normal ventral striatum using a miR expression array. Similarly, we compared the miR expression levels in dorsal striatal tissues of HD patients compared to controls. We have identified a miR signature that distinguishes normal dorsal versus normal ventral striatum, and a miR signature that distinguishes between normal and HD dorsal striatum. It is our hypothesis that the differential miR expression in normal tissue may provide clues to the cause of the increased vulnerability of MSN to mutant htt expression. We have expanded these preliminary studies by transfecting mutant htt expressing neuronal cell lines with a miR library. We have determined that over-expression of three specific miRs is protective in mutant htt expressing neurons while overexpression of one additional miRs is toxic. These data lead to the overall hypothesis of this project: Differential expression of miRs may sensitize dorsal striatum to early neuronal death and that mutant htt expression may lead to additional disregulation of miR expression and exacerbate the HD cell death phenotype. Furthermore, we hypothesize that these miRs and their target genes represent potential novel therapeutic targets for HD. This will be investigated using three specific aims: 1) To determine if manipulation of miR levels in the brain of mouse models of HD can alter disease onset and/or progression. 2) To determine if knockout of miR-155, which is increased in dorsal striatum as compared to ventral striatum, will alter HD onset and progression in a mouse model of HD. 3) To determine the downstream targets of differentially expressed miRs to identify new potential therapeutic targets for HD. Thus, the key significance of the work described in this application is to determine how a new critical regulatory pathway (i.e. miR) may both sensitize dorsal striatal neurons to cell death, as well as how mutant htt may actively alter miR expression resulting in overt activation of cell death pathways. Our hope is that by understanding what makes the dorsal striatum different (i.e. more vulnerable), as well as how mutant htt alters miR homeostasis, we should be able to both better understand the biology of HD as well as develop novel therapeutic approaches for the treatment of this devastating disease. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a devastating chronic neurodegenerative disorder. No effective treatment is available and the disease is universally fatal. This application will determine the role of small RNAs in HD, for the purpose of developing novel therapeutic strategies and enhance our understanding of the pathophysiology of the disease.